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BACKGROUND Coffee consumption is associated with a reduced risk of several chronic diseases in a dose-dependent manner. Chronic intake results in the transient appearance of bioactive phenolic metabolites in the circulatory system. However, there is a lack of information on the impact of different patterns of coffee consumption on plasma and urinary profiles of phenolic metabolites. OBJECTIVES Plasma and urinary phenolic metabolites were investigated following regular consumption of different daily dosages of coffee or cocoa-based products containing coffee (CBPCC) under a real-life setting. METHODS A repeated-dose, randomized, crossover human intervention was conducted with 21 healthy volunteers. For 1 mo, participants consumed 1) 1 cup of coffee (1C), 2) 3 cups of coffee (3C), or 3) 1 cup of coffee + 2 CBPCC twice daily (PC). Plasma and urine samples were collected over a 24-h period after each treatment. The nutrikinetics and urinary excretion of native, human phase II, and colonic metabolites were assessed. RESULTS A total of 51 (poly)phenolic metabolites were quantified, with 41 metabolites being strictly related to coffee consumption. Significant differences were observed among treatments for most of the metabolites. The metabolites present in the highest amounts were the hydroxycinnamate, phenylpropanoic acid, benzaldehyde, and benzene classes, along with (-)-epicatechin and phenyl-γ-valerolactone derivatives after PC treatment. Daily average concentrations did not exceed 200 nmol/L and were

Free fatty acid receptor-1 (FFA1) agonists have been considered for a long time as a potentially new class for the treatment of type 2 diabetes mellitus. Phenylpropanoic acid is the preferred scaffold in the development of FFA1 receptor agonists. This review analyzes the effect of structural fragments of phenylpropanoic acid-based agonists on receptor affinity, selectivity, biocompatibility, and metabolic stability. Current trends in the design of FFA1 receptor agonists are discussed.

Peroxisome proliferator-activated receptor (PPAR)α, a member of the nuclear receptor family, is a transcription factor that regulates the expression of genes related to lipid metabolism in a ligand-dependent manner, and has attracted attention as a target for hypolipidemic drugs. We have been developing phenylpropaonic acid derivatives as PPARα-targeted drug candidates for the treatment of metabolic diseases. Recently, we have developed the "ligand-exchange soaking method," which crystallizes the recombinant PPARα ligand-binding domain (LBD) as a complex with intrinsic fatty acids derived from an expression host Escherichia (E.) coli and thereafter replaces them with other higher-affinity ligands by soaking. Here we applied this method for preparation of cocrystals of PPARα LBD with its ligands that have not been obtained with the conventional cocrystallization method. We revealed the high-resolution structures of the cocrystals of PPARα LBD and the three synthetic phenylpropaonic acid derivatives: TIPP-703, APHM19, and YN4pai, the latter two of which are the first observations. The overall structures of cocrystals obtained from the two methods are identical and illustrate the close interaction between these ligands and the surrounding amino acid residues of PPARα LBD. This ligand-exchange soaking method could be applicable to high throughput preparations of co-crystals with another subtype PPARδ LBD for high resolution X-ray crystallography, because it also crystallizes in complex with intrinsic fatty acid(s) while not in the apo-form.

Methylated flavonoids possess improved bioactivities compared to their unmethylated counterparts. In this study, for the efficient production of O-methylated flavonoids from simple methylated phenylpropanoic acids, a recombinant Escherichia coli strain expressing 4-coumarate:coenzyme A ligase (4CL) from Oryza sativa and chalcone synthase (CHS) from Hordeum vulgare was constructed; this strain produced significant amount of homoeriodictyol (~ 52 mg/L) as well as a few amount of hesperetin (0.4 mg/L), respectively, from ferulic acid and 4-methylcaffeic acid. This demonstrates, for the first time, that the scarce but valuable methylated flavanones can be successfully produced from methylated phenylpropanoic acids in a microbial host via an artificial biosynthetic pathway consisting of 4CL and CHS that can accept O-methylated precursors.

This work aimed to render phenomenologically autonomous the otherwise stepwise operation of a catenane-based molecular switch, which is chemically triggered by the decarboxylation of 2-cyano-2-phenylpropanoic acid (2). Given that any amount of 2 in stoichiometric excess with respect to the catenane is consumed in a side reaction, the authors resorted to the corresponding anhydride 5, the slow hydrolysis of which, due to adventitious water in dichloromethane, continuously produces in situ the actual fuel 2. As a consequence, the machine does not require a reloading after each cycle, but switches back and forth as long as fuel is present.

The rhizome of Etlingera elatior or Wualae (Tolakinese) has many advantages on traditional remedies and cooking in Sulawesi Tenggara. To support those advantages, two secondary metabolites derived from steroid and phenylpropanoic acid classes, stigmast-4-en-6β-ol-3-one (1) and p-coumaric acid (2), respectively, have been firstly isolated and identified from the E. elatior rhizome. Isolation of these two compounds was performed using several chromatography techniques, including thin layer chromatography (TLC), vacuum liquid chromatography (VLC) and radial chromatography (RC). Identification of isolates was carried out using 1H and 13C NMR spectroscopy and comparing the spectroscopy data with the library. The potency of antibacterial of the methanol extract of Wualae rhizome and the isolates were evaluated against Pseudomonas aeruginosa ATCC 27853, Bacillus subtilis FNCC 0060, Staphylococcus aureus ATCC 25923, Escherichia coli ATCC 35218, Salmonella enterica ATCC 14028, and Streptococcus mutans ATCC 25175 using agar diffusion method. Antioxidant activity was evaluated against DPPH radicals (2,2-diphenyl-1-picrylhydrazyl). The results show that the antibacterial potential of Wualae methanol extract is better than compound 1 and 2. Furthermore, the antioxidant properties of Compound 2 (IC50 159.47 μg/mL) was stronger than the antioxidant properties of Compound 1 (IC50 219.95 μg/mL) and the methanol extract (IC50 586.38 μg/mL).

The free fatty acid receptor 1 (FFA1) is considered as a promising anti-diabetic target based on its function of glucose-stimulated insulin secretion. The previously reported compound 2 is a highly potent FFA1 agonist, but it might be suffered from poor pharmacokinetic properties because the phenylpropanoic acid is vulnerable to β-oxidation. To identify orally available analogs, we tried to block the route of β-oxidation by incorporating deuterium at phenylpropionic acid moiety. As expected, the deuterium-based analogs 3 and 4 exhibited better pharmacokinetic properties than parent compound 2. Although the difference of potency between compound 2 and 3 is quite small, the glucose-lowering effect of deuterium analog 3 was better than that of compound 2. Meanwhile, compound 3 docked well into the same binding pocket of TAK-875, and formed almost identical interactions of TAK-875 in binding site. Different from glibenclamide, a lower risk of hypoglycemia was observed in compound 3 even at the high dose of 60 mg/kg.

Although leaves of Anchietea salutaris are used in Brazilian traditional medicine, there is no available data in the literature proving its efficacy and safety. Thus, the aim of the study was to perform a meticulous botanical, phytochemical, toxicological, and pharmacological investigation of A. salutaris in Wistar rats. At first, a morphoanatomical characterization of Anchietea pyrifolia leaves and stems was performed. Then, a purified infusion (ethanol-soluble fraction obtained from A. pyrifolia [ESAP]) was obtained followed by its chemical profile elucidation. Furthermore, an acute toxicity test was performed, and the acute and prolonged diuretic and hypotensive effects were also evaluated in Wistar rats. Finally, the vasodilatory responses of ESAP in mesenteric vascular beds were investigated. The main secondary metabolites identified from ESAP were O-glycosylated flavonoids, chlorogenic acids, and phenylpropanoic acid derivatives. ESAP did not promote any toxic effects in female rats nor increased urinary excretion in male rats after a single exposure. However, ESAP significantly reduced renal elimination of sodium, potassium, and chloride after prolonged treatment. An ESAP highest dose promoted significant acute hypotension without affecting blood pressure levels after prolonged use. Furthermore, its cardiovascular effects seem to be related with the calcium-activated potassium channel activation in resistance vessels.

Free fatty acid 1 (FFA1/GPR40) has attracted extensive attention as a novel target for the treatment of type 2 diabetes for its role in the enhancement of insulin secretion with glucose dependency. Aiming to develop novel potent FFA1 agonists, a new series of phenylpropionic acid derivatives were designed and synthesized on the basis of the modification of chemical cement of TAK-875, AMG-837, and LY2881835. Among them, most promising compounds 7, 14, and 15 were obtained with EC50 values of 82, 79, and 88 nM, exhibiting a powerful agonistic activity compared to TAK-875 (95.1 nM). During Oral glucose tolerance test in normal mice, compound 7, 14, and 15 had significant glucose-lowering effect at the dose of 50 mg/kg. Furthermore, compound 15 (50 mg/kg) also significantly improved in glucose tolerance in type 2 diabetic mice. Herein, we reported the discovery and optimization of a series of potent FFA1 agonists. The discovery supported further exploration surrounding this scaffold.

A detailed study on the foamability, foam stability, foam liquid-carrying capacity, and foam morphology of two N-acyl amino acid surfactants with bovine serum albumin (BSA) and gelatin were performed by foam scanning. The results showed that the foamability of the mixed system increased gradually and then tended to be stable with increasing surfactant concentration. The foamability of the high-concentration BSA system was stronger than that of the low-concentration BSA system. The foamability and foam stability of sodium N-lauroyl phenylpropanoic acid (N-C12P)/BSA were better than those of sodium N-lauroyl propylamino acid (N-C12A)/BSA, and the foamability and foam stability of N-C12A/gelatin was better than those of N-C12P/gelatin. The liquid-carrying capacity of the foam initially increased and then decreased with increasing time, and the maximum liquid-carrying capacity increased with increasing surfactant concentration. When the concentration of the surfactant was 8 mM, the drainage rate of N-C12A/protein was higher than that of N-C12P/protein. The morphology of the bubble gradually changed from spherical to polyhedron and the number of bubbles gradually decreased with time increasing. Differences in surfactant structure and protein type had an important effect on the number and area of foam.

International audience; The objective of this work was the development of a detailed, extensive and reliable database of the metabolomes of P. vittata. Using an ultra-performance liquid chromatography-triple quadrupole tandem mass spectrometry system (UPLC-QqQ-MS/MS) and based on the knowledge of retention time and mass spectral characteristics of an in-house collection of authentic standards, we screened for the presence of a large collection of natural compounds. The database represents 359 authenticated metabolites, comprising 220 primary and 139 secondary metabolites (70 flavonoids, 16 phenylpropanoic acid derivatives, five coumarins, two stilbenoids, 14 benzoic acids, nine phenols, 20 alkaloids and three terpenoids). Comparison of the accumulation of these compounds in two tissues showed that the aerial parts were enriched in flavonols, whereas the subterranean parts were enriched in anthocyanins. The comprehensive database developed here will be beneficial in improving the understanding of the chemical basis of plant therapeutic profile using multivariate analysis, with a particular example of antioxidant activity.

Molecules : a journal of synthetic chemistry and natural product chemistry 26(4), 799 (2021). doi:10.3390/molecules26040799 special issue: "Special Issue "Designed Multiple Ligands in Drug Design and Development" / Special Issue Editors: Prof. Rosanna Maccari, Guest Editor; Prof. Rosaria Ottana, Guest Editor", Published by MDPI, Basel

Introduction: It has been reported that the phenolic metabolite 3¿-methoxycinnamic acid-4¿-sulfate generated from 5-O-caffeoylquinic acid may have potential benefits in human health. However, the variation in 3¿-and 4¿-methylation of 3¿,4¿-dihydroxycinnamic acid and its impact on the yield of this sulfate metabolite is unclear and has been poorly studied. Methods and Results: To address this aim, the excreted 3¿-methoxy and 4¿-methoxy metabolites in urine samples (24-h) are determined in 14 volunteers after an acute intake of 80 g of red-fleshed apple (RFA) or white-fleshed apple (WFA). These methoxy metabolites are also determined in the same volunteers in a second acute intake after a 6-week sustained consumption of the same products. Conclusion: Seven 3¿-methoxy and seven 4¿-methoxy metabolites are determined, i.e., the free cinnamic and corresponding phenylpropanoic acid, plus their sulfate, glucuronide, and glycine conjugates. In only six volunteers, five females and one male, is 4¿-methylation preferred over 3¿-methylation, but it is observed that an individual¿s 3¿- : 4¿-methylation ratio can change over time, and that the yield of 3¿-methoxycinnamic acid-4¿-sulfate is extremely variable, ranging from undetectable to 71% of the total C6-C3 metabolites excreted, and any benefit accruing from this metabolite will not necessarily be available to all consumers., This study was supported by the Spanish Ministry of Economy, Industry and Competitiveness through the AGL2016-76943-C2-1-R and AGL2016- 76943-C2-2-R projects (co-funded by the European Social Fund, European Union).

Quercetin is one of the main dietary flavonols, but its beneficial properties in disease prevention may be limited due to its scarce bioavailability. For this purpose, delivery systems have been designed to enhance both stability and bioavailability of bioactive compounds. This study aimed at investigating the human microbial metabolism of quercetin derived from unformulated and phytosome-formulated quercetin through an in vitro model. Both ingredients were firstly characterized for their profile in native (poly)phenols, and then fermented with human fecal microbiota for 24 h. Quantification of microbial metabolites was performed by ultra-high performance liquid chromatography coupled to mass spectrometry (uHPLC-MSn) analyses. Native quercetin, the main compound in both products, appeared less prone to microbial degradation in the phytosome-formulated version compared to the unformulated one during fecal incubation. Quercetin of both products was bioaccessible to colonic microbiota, resulting in the production of phenylpropanoic acid, phenylacetic acid and benzoic acid derivatives. The extent of the microbial metabolism of quercetin was higher in the unformulated ingredient, in a time-dependent manner. This study opened new perspectives to investigate the role of delivery systems on influencing the microbial metabolism of flavonols in the colonic environment, a pivotal step in the presumed bioactivity associated to their intake.

The free fatty acid receptor 1 (FFA1) is a potential target due to its function in enhancing of glucose-stimulated insulin secretion. The FFA1 agonist GW9508 has great potential for the treatment of type 2 diabetes mellitus, but it has been suffering from high plasma clearance probably because the phenylpropanoic acid is vulnerable to β-oxidation. To identify orally available analog without influence on the unique pharmacological mechanism of GW9508, we tried to interdict the metabolically labile group by incorporating two deuterium atoms at the α-position of phenylpropionic acid affording compound 4 (HWL-066). As expected, HWL-066 revealed a lower clearance (CL = 0.23 L-1 hr-1 kg-1 ), higher maximum concentration (Cmax = 5907.47 μg/L), and longer half-life (T1/2 = 3.50 hr), resulting in a 2.8-fold higher exposure than GW9508. Moreover, the glucose-lowering effect of HWL-066 was far better than that of GW9508 and comparable with TAK-875. Different from glibenclamide, no side-effect of hypoglycemia was observed in mice after oral administrating HWL-066 (80 mg/kg).

The free fatty acid receptor 1 (FFA1) is a potential target due to its function in enhancement of glucose-stimulated insulin secretion. Takeda’s compound 1 has robustly in vitro activity for FFA1, but it has been suffered from poor pharmacokinetic (PK) profiles because the phenylpropanoic acid is vulnerable to β-oxidation. To identify orally available agonists, we tried to interdict the metabolically labile group by incorporating two deuterium atoms at the α-position of phenylpropionic acid. Interestingly, the differences of physicochemical properties between hydrogen and deuterium are quite small, but there are many differences in the structure-activity relationship between phenylpropionic acid series and present deuterated series. Further optimizations of deuterated series led to the discovery of compound 18, which exhibited a superior balance in terms of in vitro activity, lipophilicity, and solubility. Better still, compound 18 revealed a lower clearance (CL = 0.44 L/h/kg), higher maximum concentration (Cmax = 7584.27 μg/L), and longer half-life (T1/2 = 4.16 h), resulting in a >23-fold exposure than compound 1. In subsequent in vivo pharmacodynamic studies, compound 18 showed a robustly glucose-lowering effect in rodent without the risk of hypoglycemia.

GPR120 is a promising target for the treatment of type 2 diabetes (T2DM), which is activated by free fatty acids (FFAs) and stimulates the release of glucagon-like peptide-1(GLP-1). GLP-1, as an incretin, can enhance glucose-dependent secretion of insulin from pancreatic beta cells and reduce blood glucose. In this study, a series of novel GPR120 agonists were designed and synthesized to improve the stability and hydrophilicity of the phenylpropanoic acid GPR120 agonist TUG-891. Compound 11b showed excellent GPR120 agonistic activity and pharmacokinetic properties, and could reduce the blood glucose of normal mice in a dose-dependent manner. In addition, no hypoglycemic side effects were observed even at a dose of 100 mg/kg. Moreover, 11b showed good anti-hyperglycemic effects in diet-induced obese (DIO) mice. Molecular simulation illustrated that compound 11b could enter the active site of GPR120 and interact with ARG99. Taken together, the results indicate that compound 11b might be a promising drug candidate for the treatment of T2DM.

A novel series of 5-membered heterocycle-containing phenylpropanoic acid derivatives was discovered as potent GPR120 agonists with low clearance, high oral bioavailability and in vivo antidiabetic activity in rodents.

A series of Bronsted-Lewis acidic deep eutectic solvents (DESs) of C 9 H 10 O 2 ·XZnCl 2 (X from 0.5 to 3) were synthesized by simple mixing. The DESs were characterized by infrared spectroscopy, electrospray ionization mass spectrometry, and thermogravimetric analysis. The desulfurization of a model oil was investigated using C 9 H 10 O 2 ·XZnCl 2 as the extraction agent and catalyst, and H 2 O 2 as the oxidant. The effects of the molar ratio of phenylpropanoic acid to zinc chloride, reaction temperature, oxygen to sulfur (O/S) molar ratio, and volume ratio of DESs to oil on the desulfurization rate were investigated. The optimal conditions for desulfurization were determined to be a phenylpropanoic acid to zinc chloride ratio of 2:1, a reaction temperature of 50 °C, an O/S ratio of 6, a DESs to oil volume ratio of 0.25:1, and a model oil dosage of 5 mL. Under the optimal conditions, a desulfurization rate of 99.23% in 80 min was achieved. The recyclability of the DESs was also investigated, and the results showed that the desulfurization rate decreased slightly after five runs. These results demonstrate that C 9 H 10 O 2 ·0.5ZnCl 2 DESs exhibit high desulfurization activity and stability in extraction and oxidation desulfurization systems.

The back and forth motions of a crown-ether based wheel along the axis of a bistable rotaxane are triggered by the decarboxylation of 2-cyano-2-phenylpropanoic acid and detected by the oscillation of the EPR nitrogen splitting of a dialkyl nitroxide function mounted within the macrocyclic ring. When the p-Cl derivative of the acid is used, back and forth motions are accelerated. Conversely, with p-CH3 and p-OCH3 derivatives, the back motion is strongly inhibited by the insurgence of collateral radical reactions.

We report on the syntheses of three asymmetrical zinc(II) phthalocyanine endowed with benzoic acid, phenylpropanoic acid, and phenylacetic acid units: (1), (2), and (3), respectively. Metal tungstate nanoparticles, capped with glutathione were prepared and characterized using analytical techniques. Complexes were covalently linked to nickel tungstate (NiWO4) and bismuth tungstate (Bi2WO6) through an amide bond. The complexes and the conjugates with nanomaterial were evaluated for singlet oxygen generating ability. Complexes 1–2 and their conjugates generate higher singlet oxygen compared to 3 and its corresponding conjugates. The conjugates show degradation of dibenzothiophene (DBT) in fuel with shorter half-lives and greater initial rate values compared to phthalocyanines alone.

NLRP3 inflammasome activation and subsequent release of IL-1β are being explored as a causal pathology for inflammatory and autoimmune disorders. Modulation of this pathway by the compounds from natural sources may provide a better targeted approach with improved therapeutic outcome. The study was carried out to test the ability of phenylpropanoic acid derivatives to inhibit the NLRP3 inflammasome pathway and IL-1β release. The main purpose of the study was to test the active derivatives with respect to the possible molecular interactions in-silico, effect on mRNA expression of molecular markers and, effect on released cytokine. Autodock along with SwissADME was used to carry out the in-silico studies including the prediction studies as well as molecular docking studies. The effect of test compounds on mRNA expression of important proteins was evaluated against U87MG cells using RT-qPCR. The changes in released cytokine levels was evaluated using ELISA. The tested phenylpropanoic acid derivatives had a comparable molecular docking profile to that of selected standards. The prediction studies indicated that these compounds have suitable properties to be a drug candidate. mRNA expression studies showed that the derivatives can downregulate the proteins responsible for inflammasome activation and same was reflected in ELISA when the concentration of released cytokine was evaluated. Based on the above results, phenylpropanoic acid derivatives have potential to be developed as specific NLRP3-inflammasome inhibitors.

The present study deals with synthesizing novel cellulose derivative, from modifying the carboxymethyl cellulose with amino phenylpropanoic acid (CMC-APP). The synthesized CMC-APP was evaluated as biological and anti-cancer active compound. The molecular structures of this active compound were built using the HyperChem program 7.5, together with conventional analysis (nitrogen content, FT-IR, and non-isothermal TGA analysis). Optimizing the CMC/APPA ratio was carried out as preliminary assessment step, via undetected antimicrobial activity measurement. The TEM study showed that, the synthesized cellulose CMC-APP derivative in the nano-scale particle size (range from 12.5 to 89.3nm). Among all the tested microorganisms and MCF-7 breast cancer cells, the synthesized nano-cellulose derivative is possible used as safety medicine for microbial infections and cancers. The minimal inhibitory concentration (MIC) for Gram-positive bacteria, and gram-negative bacteria are 48.82μg/mL and 97μg/mL, respectively. While, the unicellular fungi and filamentous fungi are 12.2μg/mL and 97.65μg/mL, respectively. The cytotoxic index (IC50) for MCF-7 breast cancers is 50μg/mL. Moreover, the computational study of ADMET (absorption, distribution, metabolism, elimination and toxic) properties, of the molecules showed that, this investigated nano-compound is good oral bioavailability.

Phenylpropanoids are widely used in food supplements, pharmaceuticals, and cosmetics with diverse benefits to human health. Trans-cinnamic acid or p-coumaric acid is usually used as the starting precursor to produce phenylpropanoids. Synthetic bioengineering of microbial cell factories offers a sustainable and flexible alternative method for obtaining these compounds. In this study, a constitutive expression system consisting of Rhodotorula glutinis phenylalanine/tyrosine ammonia lyase was developed to produce a phenylpropanoic acid precursor in Escherichia coli. To improve trans-cinnamic acid and p-coumaric acid production, BioBrick optimization was investigated, causing a 7.2- and 14.2-fold increase in the yield of these compounds, respectively. The optimum strain was capable of de novo producing 78.81 mg/L of trans-cinnamic acid and 34.67 mg/L of p-coumaric acid in a shake flask culture. The work presented here paves the way for the development of a sustainable and economical process for microbial production of a phenylpropanoic acid precursor.

The decarboxylation of 2-cyano-2-phenylpropanoic acid is fast and quantitative when carried out in the presence of 1?molar equivalent of a [2]catenane composed of two identical macrocycles incorporating a 1,10-phenanthroline unit in their backbone. When decarboxylation is over, all of the catenane molecules have experienced large-amplitude motions from neutral to protonated catenane, and back again to the neutral form, so that they are ready to perform another cycle. This study provides the first example of the cyclic operation of a molecular switch at the sole expenses of the energy supplied by the substrate undergoing chemical transformation, without recourse to additional stimuli. Poetry in motion: Carboxylic acid 1 was found to be a convenient fuel for the operation of a molecular switch that moves under the influence of protonation-deprotonation steps. The cyclic motions of the catenane switch were induced solely by the chemical energy supplied by the decarboxylation of 1, without recourse to additional stimuli.

The actinomycete strain Streptomyces coelicolor LY001 was purified from the sponge Callyspongia siphonella. Fractionation of the antimicrobial extract of the culture of the actinomycete afforded three new natural chlorinated derivatives of 3-phenylpropanoic acid, 3-(3,5-dichloro-4-hydroxyphenyl)propanoic acid (1), 3-(3,5-dichloro-4-hydroxyphenyl)propanoic acid methyl ester (2), and 3-(3-chloro-4-hydroxyphenyl)propanoic acid (3), together with 3-phenylpropanoic acid (4), E-cinnamic acid (5), and the diketopiperazine alkaloids cyclo(l-Phe-trans-4-OH-l-Pro) (6) and cyclo(l-Phe-cis-4-OH-d-Pro) (7) were isolated. Interpretation of nuclear magnetic resonance (NMR) and high-resolution electrospray ionization mass spectrometry (HRESIMS) data of 1&ndash, 7 supported their assignments. Compounds 1&ndash, 3 are first candidates of the natural chlorinated phenylpropanoic acid derivatives. The production of the chlorinated derivatives of 3-phenylpropionic acid (1&ndash, 3) by S. coelicolor provides insight into the biosynthetic capabilities of the marine-derived actinomycetes. Compounds 1&ndash, 3 demonstrated significant and selective activities towards Escherichia. coli and Staphylococcus aureus, while Candida albicans displayed more sensitivity towards compounds 6 and 7, suggesting a selectivity effect of these compounds against C. albicans.

Free fatty acid receptor 1 (FFA1 or GPR40) has been studied for many years as a target for the treatment of type 2 diabetes mellitus. In order to increase potency and reduce hepatotoxicity, a series of novel compounds containing imidazo[1,2-a]pyridine scaffold as GPR40 agonist were synthesized. Compound I-14 was identified as an effective agonist as shown by the conspicuous drop in blood glucose in normal and diabetic mice. It had no risk of hepatotoxicity compared with TAK-875. Moreover, good pharmacokinetic (PK) properties of I-14 were observed (CL = 27.26 ml/h/kg, t1/2 = 5.93 h). The results indicate that I-14 could serve as a possible candidate to treat diabetes.

The bioactivity of dietary polyphenols depends upon gastrointestinal and hepatic metabolism of secondary microbial phenolic metabolites generated via colonic microbiota-mediated biotransformation. A polyphenol-rich potato extract (PRPE) containing chlorogenic, caffeic, and ferulic acids and rutin was digested in a dynamic multi-reactor gastrointestinal simulator of the human intestinal microbial ecosystem (GI model). Simulated digestion showed extensive degradation of the parent compounds and the generation of microbial phenolic metabolites. To characterize the transport and metabolism of microbial phenolic metabolites following digestion, a co-culture of intestinal Caco-2 and hepatic HepG2 cells was exposed to the PRPE-derived digests obtained from the colonic vessels. Following a 2 h incubation of the digesta with the Caco-2/HepG2 co-cultures, approximately 10–15% of ferulic, dihydrocaffeic, and dihydroferulic acids and 3–5% of 3-hydroxybenzoic, 3-hydroxyphenylpropionic, and coumaric acids were observed in the basolateral side, whereas 3-hydroxyphenylacetic acid, phenylpropanoic acid, and cinnamic acid were not detected. Subsequent HepG2 cellular metabolism led to major increases in ferulic, dihydrocaffeic, 3-hydroxyphenylpropionic, and coumaric acids ranging from 160–370%. These findings highlight the importance of hepatic metabolism towards the generation of secondary metabolites of polyphenols despite low selective Caco-2 cellular uptake of microbial phenolic metabolites.

Three new glucosides of phenylpropanoic acid derivatives (micromelumosides A–C) and a new coumarin glucoside (micromelumoside D) were isolated from the aerial portions of Micromelum minutum in addition to 15 known compounds, 3,4-dihydro-1,2-secomicrominutinin 9-O-β-​ d -glucopyranside, umbelliferone-​7-​O-​α-​ l -​rhamnopyranosyl-​(1 → 6)​-​β-​ d -​glucopyranoside, scopolin, haploperoside A, (S)-peucedanol 7-O-β- d -glucopyranoside, (R)-peucedanol 7-O-β- d -glucopyranoside, decuroside V, 4-hydroxy-2,6-dimethoxyphenyl 4-O-β- d -glucopyranoside, vanilloloside, 3,5-dimethoxybenzyl alcohol 4-O-β- d -glucopyranoside, (+)-lyoniresinol 3α-O-β- d -glucopyranoside, (+)-syringaresinol 4-O-β- d -glucopyranoside, kaempferol 3-O-sophoroside, kaempferol 3-O-rutinoside, and citroside B. The structure elucidation of these compounds was based on analyses of spectroscopic data including 1D and 2D NMR.

We have discovered a novel series of isothiazole-based phenylpropanoic acids as GPR120 agonists. Extensive structure–activity relationship studies led to the discovery of a potent GPR120 agonist 4x, which displayed good EC50 values in both calcium and β-arrestin assays. It also presented good pharmaceutical properties and a favorable PK profile. Moreover, it demonstrated in vivo antidiabetic activity in C57BL/6 DIO mice. Studies in WT and knockout DIO mice showed that it improved glucose handling during an OGTT via GPR120. Overall, 4x possessed promising antidiabetic effect and good safety profile to be a development candidate.

The free fatty acid receptor GPR40 is predominantly expressed in pancreatic β-cells and enhances insulin secretion in a glucose dependent manner. Therefore, GPR40 agonists are possible novel insulin secretagogues with reduced or no risk of hypoglycemia for the treatment of type 2 diabetes mellitus (T2DM). Chemically and structurally diverse GPR40 agonists with high safety are pursued for the clinical development of GPR40-based pharmacotherapeutics. Herein we report our design and discovery of a new chemotype of GPR40 agonists free of the typical phenylpropanoic acid scaffold. The thiophen-2-ylpropanoic acid containing GPR40 modulators functioned as full agonists with high-efficacy response (Emax) and reduced lipophilicity. Significantly, the lead compound in this series, (R)-7k, exhibited more potent in vitro glucose-stimulated insulin secretion and in vivo glucose-lowering effects (10 mg/kg, po) than the GPR40 partial agonist TAK-875, which was once in phase III clinical trials, and high selectivity over the relevant receptors GPR120 and PPARγ.